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Baltimore Highlands, MD, United States

Li Q.,Peking University | Li G.,Peking University | Lan X.,Peking University | Zheng M.,Peking University | And 5 more authors.
Journal of Biological Chemistry | Year: 2010

Proliferation of vascular smooth muscle cells (VSMCs) is a primary mechanism underlying cardiovascular proliferative disorders. Phosphoinositide 3-kinase (PI3K)-Akt (or protein kinase B) axis has been assigned at the center of pathways that regulate cell proliferation. Here we demonstrate that enhanced PI3K-Akt signaling by mitogenic stimulation or arterial injury profoundly elevates expression of receptor interacting protein 3 (RIP3) in primary cultured rat VSMCs and in vivo and that the up-regulation of RIP3 leads to VSMC growth arrest and apoptosis via inhibiting the PI3K-Akt signaling pathway, thereby alleviating balloon injury-induced neointimal formation. Specifically, mitogenic stimulation with platelet-derived growth factor-BB or angiotensin II leads to a profound increase in RIP3 expression, which is abolished by inhibition of PI3K or Akt, and increased PI3K-Akt signaling by expression of a constitutively active PI3K mutant also elevates RIP3 expression. Importantly, adenoviral overexpression of RIP3 not only triggers apoptosis but also causes cell cycle arrest atG1/G0 phases that is associated with suppressed Akt activation. In sharp contrast, RIP3 gene silencing enhances serum- and platelet-derived growth factor-induced cell proliferation and Akt activation. In vivo adenoviral gene delivery of rat RIP3 (rRIP3) increased apoptosis and reduced VSMC proliferation, thus, effectively alleviating balloon injury-induced neointimal formation. The growth-suppressive and pro-apoptotic effects are independent of rRIP3 Ser/Thr kinase activity, because overexpression of a kinase-inactive mutant of rRIP3, similar to its wild type, is sufficient to induce growth arrest and apoptosis. These findings reveal a novel growth-suppressive action of RIP3, marking RIP3 as an important factor to prevent excessive mitogenic stimulation- or injury-induced vascular smooth muscle cells hyperplasia.

Woodward O.M.,Johns Hopkins University | Liu C.-T.,Boston University | Lu X.,Boston University | Nalls M.A.,U.S. National Institute on Aging | And 23 more authors.
Human Molecular Genetics | Year: 2011

Serum urate concentrations are highly heritable and elevated serum urate is a key risk factor for gout. Genome-wide association studies (GWAS) of serum urate in African American (AA) populations are lacking. We conducted a meta-analysis of GWAS of serum urate levels and gout among 5820 AA and a large candidate gene study among 6890 AA and 21 708 participants of European ancestry (EA) within the Candidate Gene Association Resource Consortium. Findings were tested for replication among 1996 independent AA individuals, and evaluated for their association among 28 283 EA participants of the CHARGE Consortium. Functional studies were conducted using 14C-urate transport assays in mammalian Chinese hamster ovary cells. In the discovery GWAS of serum urate, three loci achieved genome-wide significance (P < 5.0 × 10 -8): a novel locus near SGK1/SLC2A12 on chromosome 6 (rs9321453, P = 1.0 × 10 -9), and two loci previously identified in EA participants, SLC2A9 (P = 3.8 × 10 -32) and SLC22A12 (P = 2.1 × 10 -10). A novel rare non-synonymous variant of large effect size in SLC22A12, rs12800450 (minor allele frequency 0.01, G65W), was identified and replicated (beta 21.19 mg/dl, P = 2.7 × 10 -16). 14C-urate transport assays showed reduced urate transport for the G65W URAT1 mutant. Finally, in analyses of 11 loci previously associated with serum urate in EA individuals, 10 of 11 lead single-nucleotide polymorphisms showed direction-consistent association with urate among AA. In summary, we identified and replicated one novel locus in association with serum urate levels and experimentally characterize the novel G65W variant in URAT1 as a functional allele. Our data support the importance of multi-ethnic GWAS in the identification of novel risk loci as well as functional variants. © The Author 2011. Published by Oxford University Press. All rights reserved.

Pulkki J.,University of Tampere | Pulkki J.,Gerontology Research Center | Tynkkynen L.-K.,University of Tampere
Ageing and Society | Year: 2016

This study examines discursive constructions of older people by analysing the talk of members of parliament in parliamentary discussions in Finland. While the perceptions of older people that are constructed in various public and private arenas have been relatively widely examined, the talk of political decision makers has not been studied to any large extent. However, decision makers' understandings of older people are likely to influence the ways in which service systems are developed and services organised for older people. The parliamentary discussions examined in this study were related to the process of enacting legislation to secure services for older people. Using discourse analysis, three ways of constructing older people-as 'the dependent', 'the active' and 'the deserving'-are identified. Although the results are to some extent in accordance with previous findings, indicating that older people are constructed as either totally dependent and passive or extremely active, this study also breaks this dichotomous view and highlights the overlap between those constructions. Nonetheless, the picture of older people remains fairly one-dimensional. There was an absence of recognition of diversity among older people, which might inhibit the development of a customer-oriented service system. © 2014 Cambridge University Press.

Portegijs E.,Gerontology Research Center | Read S.,London School of Hygiene and Tropical Medicine | Pakkala I.,GeroCenter Foundation for Research and Development | Kallinen M.,Central Finland Central Hospital | And 6 more authors.
Journal of Aging and Physical Activity | Year: 2014

Our aim was to study the effects of sense of coherence (SOC) on training adherence and interindividual changes in muscle strength, mobility, and balance after resistance training in older people with hip fracture history. These are secondary analyses of a 12-week randomized controlled trial of progressive resistance training in 60- to 85-year-old community-dwelling people 0.5-7 years after hip fracture (n = 45; ISRCTN34271567). Pre- and posttrial assessments included SOC, knee extension strength, walking speed, timed up-and-go (TUG), and Berg Balance Scale (BBS). Group-by-SOC interaction effects (repeated-measures ANOVA) were statistically significant for TUG (p = .005) and BBS (p = .040), but not for knee extension strength or walking speed. Weaker SOC was associated with poorer training adherence (mixed model; p = .009). Thus, more complicated physical tasks did not improve in those with weaker SOC, independently of training adherence. Older people with weaker SOC may need additional psychosocial support in physical rehabilitation programs to optimize training response © 2014 Human Kinetics, Inc.

Nevalainen T.,University of Tampere | Nevalainen T.,Gerontology Research Center | Kananen L.,University of Tampere | Kananen L.,Gerontology Research Center | And 11 more authors.
Age | Year: 2015

Aging is associated with a pro-inflammatory state, often referred to as inflammaging. The origin of the pro-inflammatory mediators and their role in the pathogenesis of the aging-associated diseases remain poorly understood. As aging is also associated with profound changes in the transcriptomic and epigenetic (e.g., DNA methylation) profiles of cells in the peripheral blood, we analyzed the correlation of these profiles with inflammaging using the “classical” marker interleukin-6 as an indicator. The analysis of the whole-genome peripheral blood mononuclear cell (PBMC) gene expression revealed 62 transcripts with expression levels that significantly correlated with the plasma interleukin-6 (IL-6) levels in men, whereas no correlations were observed in women. The Gene Ontology analysis of plasma IL-6-associated transcripts in men revealed processes that were linked to the inflammatory response. Additionally, an Ingenuity Pathway Analysis (IPA) pathway analysis identified Tec kinase signaling as an affected pathway and upstream regulator analysis predicted the activation of IL-10 transcript. DNA methylation was assessed using a HumanMethylation450 array. Seven genes with expression profiles that were associated with the plasma IL-6 levels in men were found to harbor CpG sites with methylation levels that were also associated with the IL-6 levels. Among these genes were IL1RN, CREB5, and FAIM3, which mapped to a network of inflammatory response genes. According to our results, inflammaging is manifested differently at the genomic level in nonagenarian men and women. Part of this difference seems to be of epigenetic origin. These differences point to the genomic regulation of inflammatory response and suggest that the gender-specific immune system dimorphism in older individuals could be accounted for, in part, by DNA methylation. © 2015, American Aging Association.

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